More formally, it is classified under the AML-M7 category of the French-American-British classification[2] and by the World Health Organization of 2016 in the AML-Not Otherwise Specified subcategory.

[3] Acute megakaryoblastic leukemia falls into three distinct groups which differ in underlying causes, ages of presentation, responses to therapy, and prognoses.

[7] Various GATA1 mutations that cause this gene to make GATA1-S but unable to make GATA1 result in the excessive proliferation of platelet precursor cells, reductions in the levels of circulating blood platelets, mild reductions in the levels of circulating red blood cells, and the development of transient myeloproliferative disease (TMD).

[6] TMD is a disorder involving the excessive proliferation of non-malignant megakaryoblasts and descendent cells due to the cited truncating mutations in the GATA1 gene.

[7] Down syndrome fetuses[8] and neonates[9] with one of the cited types of GATA1 truncating mutations are in rare cases asymptomatic (i.e. silent TMD) but more commonly exhibit in utero or during the first months of live accumulations of immature megakaryoblasts in, and sometimes life-threatening injury to, the fetal blood-forming organ, the liver, and other tissues.

[10] At least one but probably several of these mutations, whether occurring in individuals with silent or symptomatic TMD, are presumed responsible for or to contribute to the development of DS-AMKL.

[9] In cases of advanced disease, individuals with DS-AMKL may present with signs and symptoms that are more typical of acute myeloid leukemic diseases such as liver enlargement, spleen enlargement,[13] leukemia cutis (i.e. skin nodules caused by leukemic infiltrates), or leukostasis (i.e. an emergency situation in which excessive elevations in circulating blast (i.e. early precursor) cells plug the microcirculation to cause life-threatening heart, lung, and neurological dysfunctions).

An irregular cytoplasmic border is often noted in some of the megakaryoblasts and occasionally projections resembling budding atypical platelets are present.

[1] Where indicated and available, the diagnosis of DS-AMKL is further supported by; immunophenotyping analysis using monoclonal antibody directed against megakaryocyte restricted antigen (CD41 and CD61)[16] and DNA sequencing to detect GATA1 mutations that are projected to cause the gene to make GATA1-S but not GATA1 transcription factors.

This causes an over-active Notch signaling pathway and, among other abnormalities, expansion of fetal hematopoiesis and development of AMKL in a small percentage of adult mice.

[18] Except for the lack of Down syndrome, no history of TMD, and occurrences in children that can be >4 years of age, individuals with non-DS-AMKL present with many of the symptoms, signs, and hematological findings seen in DS-AMKL.

[1] The diagnosis of non-DS-AMKL is made in children who do not have Down syndrome but exhibit the same clinical symptoms, signs, hematological abnormalities, and specialized laboratory findings seen in DS-AMKL.

[1] Non-DS-AMKL has many clinical and laboratory features similar to and must be distinguished from Acute panmyelosis with myelofibrosis, a disorder characterized by bone marrow fibrosis, abnormal megakaryocytes, macrocytic erythropoiesis, defects in neutrophil production, reduced blood levels of most circulating cells (i.e. pancytopenia), and low levels of circulating blast cells.

Analyses of circulating and bone marrow blast cells for features of AMKL (see Diagnosis section of DS-AMKL) and genetic aberrations is helpful in distinguishing the two diseases.

[1] Similar to DS-AMKL treatment regimens,[17] allogenic rather than autologous stem cell bone marrow transplantation should be considered in non-DS-AMKL cases that have relapsed following their first chemotherapy-induced complete remission.

Further studies may indicate that this recent cancer chemotherapy regimen plus allogenic bone marrow transplantation in cases which relapse after the first remission are the preferred treatment for non-DS-AMKL.

[1] Adult-AMKL can result from the progression of other myeloproliferative neoplasms (MPN) viz., chronic myelogenous leukemia, polycythemia vera, essential thrombocytosis, and primary myelofibrosis.

Aberrations in the latter two chromosomes are also commonly seen in an AML that is associated with myelodydplastic-related changes (i.e. predominance of immature blood cells in the bone marrow).

Adult-AMKL may occur in individuals who have a prior diagnosis of and/or present with chronic myelogenous leukemia, polycythemia vera, essential thrombocytosis, primary myelofibrosis, or mediastinal germ cell tumor.

[20] Cases of the disease not associated with mediastinal germ cell tumors occur in adults who as a group have older median age centering around those 50–70 years old.

The disorder is far more fulminant than non-DS-AMKL and DS-AMKL and generally presents with more serious hematological symptoms (e.g. anemia-related) and a much higher incidence of extramedullary manifestations (e.g. organ enlargement, leukemia cutis) than seen in the other two forms of AMKL.

Major improvements in these statistics will likely require new approaches directed at the underlying mechanisms driving the disease.